Process for Manufacturing Substituted 5-Methoxymethylpyridine-2,3-Dicarboxylic Acid Derivatives

ABSTRACT

A process for manufacturing a 2,3-disubstituted-5-methoxymethylpyridine of formula (I), where Z is H or halogen; Z 1  is H, halogen, CN or NO 2 ; Y 2  is OM, and M is an alkali metal or an alkaline earth metal, comprises the step of: (i) reacting a compound of formula (II) where Q is a tertiary aliphatic or cyclic, saturated, partially unsaturated or aromatic amine; Z is H or halogen; Z 1  is H, halogen, CN or NO 2 ; Y 1  and Y 2  are each independently OR 1 , NR 1 R 2 , or when taken together Y 1 Y 2  is —O—, —S— or —NR 3 —; R 1  and R 2  are each independently H, C 1 -C 4  alkyl optionally substituted with C 1 -C 1  alkoxy or phenyl optionally substituted with one to three C 1 -C 4  alkyl groups, C 1 -C 4  alkoxy groups or halogen atoms, or phenyl optionally substituted with one to three C 1 -C 4  alkyl groups, C 1 -C 4  alkoxy groups or halogen atoms; R 3  is H or C 1 -C 4  alkyl, in a methanol/H 2 O mixture, comprising at least 20% by weight H 2 O (based on the sum of water and bromide (II)), with a base comprising MOCH 3  and/or MOH, where M is alkali metal or alkaline earth metal, under pressure in a closed vessel at a temperature of from 75 to 110° C. Compounds of formula (I) are useful intermediates in the synthesis of herbicidal imidazolinones, like imazamox.

The invention relates to a process for manufacturing 5-methoxymethylpyridine-2,3-dicarboxylic acid derivatives and further conversion of these compounds to herbicidal 5-substituted-2-(2-imidazolin-2-yl)nicotinic acids, such as imazamox.

Derivatives of 2-(2-imidazolin-2-yl)nicotinic acids, like imazamox (2-[(RS)-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl]-5-methoxymethylnicotinic acid),

are useful selective herbicides which act as ALS-inhibitors and can be used in pre- and post-emergence applications.

Various processes for the synthesis of these compounds are known from the literature, see e.g. EP-A 0 322 616, U.S. Pat. No. 5,378,843, U.S. Pat. No. 5,760,239, EP-A 0 933 362 or Q. Bi et al, Modern Agrochemicals 6(2)(2007) 10-14.

U.S. Pat. No. 5,378,843 discloses the synthesis of 5-(mehoxymethyl)-2,3-pyridinedicarboxylic acid by reaction of [(5,6-dicarboxy-3-pyridyl)methyl]trimethylammonium bromide di-methyl ester with sodium methoxide/methanol and NaOH/water, followed by acidification.

U.S. Pat. No. 5,760,239 discloses an improved method for the conversion of 5,6-dicarboxyl-3-pyridylmethyl ammonium halide to 5-(alkoxymethyl)pyridine-2,3-dicarboxylate salt via a single step closed reaction with the appropriate alcohol and a base at a temperature of about 120 to 180° C.

Although synthesis on an industrial scale is carried out by these methods there is still room for improvement, specifically in view of economical and ecological aspects, such as overall yield improvement or the avoidance of certain solvents or reagents.

One task of the invention is to provide an improved process for manufacturing 5-methoxymethylpyridine-2,3-dicarboxylic acids or carboxylates. A further task of the invention is to provide an improved process for converting these compounds to herbicidal 2-(2-imidazolin-2-yl)nicotinic acids or derivatives thereof.

It has been found that the methoxylation of 5,6-disubstituted-3-methylpyridines and further reaction with tertiary amines can be significantly improved by working in a system methanol/water and methanolate or a mixture of methanolate and hydroxide under pressure at a temperature of about 75 to 110° C.

Accordingly, in one aspect of the invention there is provided a process for manufacturing a 2,3-disubstituted-5-methoxymethylpyridine of formula (I),

where Z is H or halogen; Z¹ is H, halogen, CN or NO₂;

Y is OM, and

M is H, an alkali metal or an alkaline earth metal, comprising the step of: (i) reacting a compound of formula (II)

where

-   Q is a tertiary aliphatic or cyclic, saturated, partially     unsaturated or aromatic amine; -   Z is H or halogen; -   Z¹ is H, halogen, CN or NO₂; -   Y¹ and Y² are each independently OR¹, NR¹R², or when taken together     Y¹Y² is —O—, —S— or —NR³—; -   R¹ and R² are each independently H,     -   C₁-C₄ alkyl optionally substituted with C₁-C₄ alkoxy or phenyl         optionally substituted with one to three C₁-C₄ alkyl groups,         C₁-C₄ alkoxy groups or halogen atoms, or     -   phenyl optionally substituted with one to three C₁-C₄ alkyl         groups, C₁-C₄ alkoxy groups or halogen atoms; -   R³ is H or C₁-C₄ alkyl,     in a methanol/H₂O mixture, comprising at least 20% by weight H₂O     (based on the sum of water and bromide (II)), with a base comprising     MOCH₃ and/or MOH, where M is alkali metal or alkaline earth metal,     under pressure in a closed vessel at a temperature of from about 75     to 110° C.

In a further aspect of the invention there is provided a process for preparing a herbicidal imidazolinone compound of formula (III),

wherein

-   Z, Z¹ are as defined in formula (I); -   R⁴ is C₁-C₄ alkyl; -   R⁵ is C₁-C₄ alkyl, C₃-C₆ cycloalkyl or R⁴ and R⁵, when taken     together with the atom to which they are attached, represent a C₃-C₆     cycloalkyl group optionally substituted with methyl, and -   R⁶ is hydrogen; a group of the formula —N═C (lower alkyl)₂; C₁-C₁₂     alkyl optionally substituted with one of the following groups: C₁-C₃     alkoxy, halogen, hydroxyl, C₃-C₆-cycloalkyl, benzyloxy, furyl,     phenyl, halophenyl, lower alkyl-phenyl, lower alkoxyphenyl,     nitrophenyl, carboxyl, lower alkoxycarbonyl, cyano or tri lower     alkylammonium; C₃-C₁₂ alkenyl optionally substituted with one of the     following groups: C₁-C₃ alkoxy, phenyl, halogen or lower     alkoxycarbonyl or with two C₁-C₃ alkoxy groups or two halogen     groups; C₃-C₆-cycloalkyl optionally substituted with one or two     C₁-C₃ alkyl groups; or     -   a cation preferably selected from the group consisting of alkali         metals, alkaline earth metals, manganese, copper, iron, zinc,         cobalt, lead, silver, nickel, ammonium and organic ammonium;         comprising the steps of: -   (i) preparing a compound of formula (I) as described above, -   (ii) converting the compound of formula (I) into the herbicidal     compound of formula (III).

The process of the invention leads to higher yields, higher productivity (higher space time yields, lower fixed costs), lower raw material costs (NaOH is cheaper than Na-methylate) and an improved selectivity for the compounds of formula (I). It allows for lower temperatures, higher water contents and shorter reaction times.

Preferred are compounds of formula (I) where the symbols have the following meanings:

Z is preferably H. Z¹ is preferably H. Y is preferably OH.

Preferably, all symbols in formula (I) have the preferred meanings.

A particularly preferred compound of formula (I) is the compound of formula (Ia):

The compounds of formula (II) and their preparation are known, e.g. from U.S. Pat. No. 5,378,843.

Preferred compounds of formula (II) are the ones leading to the preferred compounds of formula (I). Preferably Y¹, Y² are OR¹ with R¹ being C₁-C₄ alkyl. It is understood that due to the presence of water partial hydrolysis of the diester (or other groups) may take place.

-   Q is preferably

-   Z² is O, S or NR¹²; -   R¹² is C₁-C₄ alkyl; -   R⁷ and R⁸ are each independently hydrogen, halogen, C₁-C₄ alkyl or     C₁-C₄ alkoxy, or, when taken together, R⁷ and R⁸ form a 5- or     6-membered saturated or unsaturated ring optionally interrupted by     O, S, or NR¹² and optionally substituted with one to three halogen     atoms, C₁-C₄ alkyl groups or C₁-C₄ alkoxy groups, and -   R⁹, R¹⁰ and R¹¹ are each independently C₁-C₄ alkyl, or R⁹ and R¹⁰,     when taken together, form a 5- or 6-membered ring in which R⁹R¹⁰, is     represented by the structure: —(CH₂)_(n)—, optionally interrupted by     O, S or NR⁹, where n is an integer of 3, 4 or 5, provided R¹¹ is     C₁-C₄ alkyl. -   Q⁺ is more preferably ^(⊕)NR⁹R¹⁰R¹¹ or pyridinium, and -   R⁹, R¹⁰ and R¹¹ are more preferably each independently C₁-C₄ alkyl,     or R⁹ and R¹⁰, when taken together, form a 5- or 6-membered ring in     which R⁹R¹⁰, is represented by the structure: —(CH₂)_(n)—,     optionally interrupted by O, S or NR¹², where n is an integer or 3,     4 or 5, provided R¹¹ is C₁-C₄ alkyl; in particular preferably R⁹,     R¹⁰ and R¹¹ are C₁-C₄ alkyl.

A particularly preferred compound of formula (II) is the compound of formula (IIa):

The reaction is carried out in a solvent mixture comprising methanol and at least 20% by weight of water (based on the sum of water and bromide (II)). Preferably the amount of water is from about 25 to about 75%, more preferably 30 to 70%, in particular from about 40 to about 50%. The remainder of the solvent mixture is methanol and up to about 50%, preferably up to about 20% of further solvents, preferably selected from toluene, chlorobenzene and ethanol.

The weight ratio of methanol to bromide (II) is generally in the range of from 0.5-25:1, preferably 1-20:1, more preferred 1-10:1, in particular 2-3:1.

The base comprises MeOM, MOH or a mixture of MeOM and MOH where M is alkali metal or alkaline earth metal, preferably Na or K, in particular Na. In cases of mixtures MeOM/MOH M can be the same or different, preferably it is the same.

If MeOM is present, the molar ratio of MeOM, preferably MeONa, to bromide (II) is generally in the range of 1-10:1, preferably 1-7.5:1, more preferably 1.25-7:1, in particular 1.25-2:1.

If MOH is present, the molar ratio of MOH, preferably NaOH, to bromide (II) is generally in the range of 0.5-10:1, preferably 1-7:1, more preferably 3-5:1. If a mixture of MeOM and MOH is used as base the molar ratio of MOH to bromide (II) is generally in the range of 0.5-7.5:1, preferably 1-5:1, more preferably 3-5:1. In one preferred embodiment no MOH is added to the reaction mixture. For economical reasons it is advantageous to use an excess of MOH with respect to MeOM. In another preferred embodiment, only MOH is used in a ratio of 3-10:1, more preferred 4-7:1, more preferred 4.5-6:1.

The molar ratio of total base added/bromide (II) is generally from about 2.5-10:1, preferably from about 3-7:1, particularly preferred from about 4.5-6:1. MeOM is typically added dissolved in methanol. MOH is typically added dissolved in water.

The reaction is carried out at a temperature in the range of from about 75 to 110° C., preferably in the range of from about 80 to 105° C., more preferably in the range of from about 80 to 100° C.

The reaction is carried out in a closed vessel, e.g. in a Parr pressure reactor, at an elevated pressure which is generally in the range of from about 1.01 to 5.00 bar, preferably of from about 1.02 to 4.00 bar, in particular of from about 1.03 to 3.50 bar. In a preferred embodiment no external pressure is applied, and the reaction is carried out at the pressure building up from the solvents at the reaction temperature in the closed vessel.

The reaction time is generally in the range of from about 5 to 20 h, preferably in the range of from about 6 to 9 h, in particular about 8 h.

In a preferred embodiment bromide (II), containing from about 25 to 75% by weight water (based on the sum of water and bromide (II)), is taken up in methanol, aqueous NaOH is slowly added at a temperature in the range of from about 25 to 40° C., followed by NaOCH₃ in methanol which is slowly added at a temperature in the range of from about 40 to 50° C. The reaction mixture is then heated to the reaction temperature (typically 80 to 100° C.) in a pressure reactor, which is closed, whereupon pressure builds up as the reaction temperature is reached.

After completion of the reaction the mixture is cooled down and can be worked up according to known procedures, e.g. by cooling, treatment with an acid, such as sulfuric acid, until compound (I) precipitates and can be filtered off.

In a preferred embodiment of the invention there is provided a process for manufacturing compounds of formula (I), comprising the steps of

-   (i-1) reacting a compound of formula (IV),

wherein the symbols have the meaning given in formula (II), except that Y¹, Y² are not OH, with bromine in the presence of a radical initiator in a solvent mixture comprising an aqueous phase and an organic phase, where the organic phase comprises a solvent selected from 1,2-dichloroethane, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene and tetrachloromethane, and where the pH-value of the aqueous phase is from 3 to <8, to obtain a 3-bromomethyl-5,6-disubstituted pyridine compound (V),

wherein Y¹, Y², Z and Z¹ have the meanings given in formula (II), except that Y¹, Y² are not OH, and

-   (i-2) reacting the bromo compound of formula (V) with a tertiary     amine Q in a solvent at a temperature range of about 0 to 100° C. to     obtain ammonium salt (II), and -   (i-3) reacting ammonium salt (II) in a methanol/H₂O mixture,     comprising with a base comprising MOCH₃ and MOH, where M is alkali     metal, under pressure in a closed vessel at a temperature of from     about 75 to 110° C.

In step (i-1) the molar ratio of pyridine compound (IV) to bromine is generally in the range of 1:0.5-1.2, preferably 1:0.6-1.0, more preferably 1:0.7-0.95.

It is also possible to work with half the equivalents of bromine, and to generate bromine in the reaction mixture from HBr with an oxidation agent like H₂O₂.

Suitable free-radical generators for initiating the reaction are those which decompose at the selected reaction temperature. Examples of preferred initiators are free-radical generators, such as azo compounds and peroxides. It is also possible, however, to use redox systems, especially those based on hydroperoxides, such as cumene hydroperoxide.

Radical initiators suitable for use in the method of the invention include 2,2′-azobisisobutyronitrile, 2,2′-azobis(2-methylbutanenitrile), 2,2′-azobis(2,4-dimethyl-pentanenitrile), 1,1′-azobis(cyclohexanecarbonitrile), organic and inorganic peroxides such as dilauroyl peroxide hydrogen peroxide, tert-butylperoxy-pivalate, benzoyl peroxide and the like, with 2,2′-azobisisobutyronitrile, 2,2′-azobis(2-methylbutanenitrile) and dilauroyl peroxide being preferred, and with 2,2′-azobisisobutyronitrile and 2,2′-azobis(2-methylbutanenitrile) being particularly preferred.

The molar ratio of initiator to bromine is preferably in the range of 0.04-0.15:1, more preferably 0.06-0.10:1.

The organic solvent is selected from the group consisting of 1,2-dichloroethane, chlorobenzene 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene and tetrachloromethane, preferably 1,2-dichloroethane and chlorobenzene. 1,2-dichloroethane is particularly preferred. Mixtures, in particular of the dichlorobenzenes, are also possible.

The amount of organic solvent may vary to a large extent. Preferably 900 to 2000 g, more preferably 1000 to 1300 g, organic solvent per mol of compound (II) are employed.

The reaction mixture comprises an organic phase and an aqueous phase. The amount of the aqueous phase may vary to a large extent. Preferably 140 to 500 g, more preferably 140 to 300 g, particularly 150 to 200 g of water per mol of the compound of formula (II) are employed.

During the course of the reaction the pH-value of the aqueous phase is kept in the range of from 3 to <8, preferably of from 3 to 7, more preferably of from 4 to 7. Control of the pH-value can be achieved by adding a suitable base, preferably an inorganic base such as a hydroxide of an alkali metal, e.g. NaOH, or an alkaline earth metal. Aqueous NaOH is a preferred base, particularly in diluted form (e.g. containing 5-20 wt.-% NaOH).

To achieve the desired control of the pH-value the base may be added continuously over the course of the reaction, or the pH-value is checked continuously and base is added by a connected automated dosage device.

In one preferred embodiment step (i-1) of the reaction is carried out by dissolving the compound (IV) in the organic phase and adding water to form the aqueous phase.

The initiator is added as pure compound or in solution, at room temperature or at reaction temperature after heating. Depending on the initiator decomposition temperature, a part or even the full amount of the initiator have to be added before the start of the bromine dosage. The amount of starter that has to be added during the bromine addition is also depending on the decomposition temperature. A minimum concentration of free radicals should be always available during the bromination reaction.

For 2,2′-azobis(2-methylbutanenitrile) a solution with initiator in an organic solvent is added. Slow addition of bromine as well as the base to control the pH-value can be started at the same time or some time later. It is preferred to start the bromine/base dosage later in order to have a sufficient amount of free radicals in the mixture when the bromination reaction starts. After completion of the reaction the mixture is cooled and the phases are separated.

The reaction is generally carried out at a temperature of about 50 to about 120° C., preferably about 60 to about 90° C.

The reaction may be carried out under atmospheric pressure or under excess pressure of up to 6 bar. Atmospheric pressure is preferred.

The reaction time (for step (i-1)) differs with the reaction parameters but is generally between 1 and 24 h.

In order to improve overall yield and enhance selectivity of the reaction, i.e. to reduce formation of the undesired dibromo and tribromo byproducts, it is preferred to carry out the reaction only up to a conversion of 5 to 60% (based on the amount of compound (IV)), preferably 30 to 55%. In one preferred embodiment the reaction is carried out up to a conversion of about 50% (based on compound (IV)). The degree of conversion may be checked by standard methods known to those skilled in the art, e.g. by HPLC analysis.

When the desired degree of conversion is reached the reaction is stopped and the phases are separated.

The organic phase, containing the product of step (i-1), compound (V), unreacted starting material (IV) and the dibromo and tribromo byproducts, may be extracted with water to remove water soluble impurities like acids and bromide. Product (III) can be isolated by known procedures, it is preferred, however, to use the organic phase without further work-up for the reaction with the tertiary amine Q (step (i-2)).

It is also possible to extract the aqueous phase with the organic solvent and to combine the organic phases in order to increase the yield of compound (V).

In step (i-2) of the reaction compound (V) is reacted with a tertiary amine Q to obtain the ammonium compound (II).

Preferred tertiary amines Q follow from the preferred meanings of Q in formula (II) above, i.e., pyridine and tertiary alkyl amines NR⁹R¹⁰R¹¹ are more preferred,

where

-   R⁹, R¹⁰ and R¹¹ are each independently C₁-C₄ alkyl, or, R⁹ and R¹⁰,     when taken together, form a 5- or 6-membered ring in which R⁹R¹⁰ is     represented by the structure: —(CH₂)_(n)—, optionally interrupted by     O, S or NR¹², where n is an integer of 3, 4, or 5, provided R¹¹ is     C₁-C₄ alkyl, and -   R¹² is C₁-C₄ alkyl.

Trimethylamine, NMe₃, is particularly preferred.

Generally an excess of tertiary amine is used. Typically 1.1 to 2, preferably 1.05 to 1.5 equivalents of tertiary amine per equivalent of compound (V) are employed.

Generally the tertiary amine, optionally dissolved in a solvent, is slowly added to the solution of compound (V), whereupon the salt (II) forms and precipitates. In case of the preferred amine NMe₃, which is gaseous at room temperature, it is preferred to work in a closed vessel and charge the gaseous amine or the liquidified amine under pressure to the solution of compound (V).

Step (i-2) is preferably carried out at a temperature of about 0 to 70° C., more preferably 5 to 70° C., particularly preferred 5 to 40° C. The reaction can be carried out at ambient pressure or at elevated pressure. In a preferred embodiment, the reaction is carried out in a closed vessel at the pressure of the solvent and/or amine building up at the reaction temperature.

Work up of the reaction mixture and isolation of the ammonium compound (II) can be carried out by conventional methods, e.g. compound (II) can be filtered off.

In a preferred embodiment water is added to the reaction mixture to dissolve the product, compound (II), and aqueous phase and organic phase are separated. The water phase may be further extracted with organic solvent in order to increase the purity of the product (II), and to increase the yield of recovered starting material (V) in the organic phase. The amount of water must be sufficient to form an aqueous phase and is preferably chosen to form a 20 to 45% by weight solution of compound (II) in the aqueous phase.

Ammonium compound (II) can be isolated from the aqueous phase by known methods. In a preferred embodiment compound (II) is not isolated and the aqueous phase obtained from step (i-2) is used in subsequent reactions without further workup. This is possible and advantageous, since a large amount of water is tolerated in the methoxylation process of the invention. However, it is also possible to mix the aqueous phase with a solvent that forms an azeotrope with water, e.g. toluene, and water is removed by azeotropic distillation. The resulting suspension of compound (II) can be used for further reactions.

In a further preferred embodiment, after separation of compound (V), the organic phase from step (i-2) containing up to 80% of starting material (IV) (based on the original amount used in step (i-1)) is recovered and recycled in the reaction process of step (i-1). Preferably further starting material (IV) is added to compensate for the amount converted in previous step (i-1). Thus, in principle, the organic phase of step (i-1) can be recycled any amount of times, however, due to an accumulation of byproducts, mainly the di- and tribromination product of compound (IV), up to 20, preferably up to 10 cycles are generally feasible.

In a preferred embodiment of the cyclic reaction process no additional starting material (IV) is added in the last cycle to improve the overall yield and conversion rate.

In a further embodiment of the cyclic reaction process a certain amount of the organic phase, preferably about 5 to 20% by weight, are removed to reduce or suppress accumulation of byproducts in the organic phase. In this embodiment of the invention there is virtually no limit to the number of cycles in which the organic phase can be used.

The compounds of formula (I) are valuable intermediates in organic synthesis. They are especially useful for conversion to herbicidal imidazolinone compounds (III).

Further conversion of compound (I) to herbicidal imidazolinones (III) can be achieved by methods known in the art.

Methods that may be used to create the imidazolinone herbicides are illustrated in the book “The Imidazolinone Herbicides” edited by D. L. Shaner and S. L. O'Connor, published 1991 by CRC Press, Boca Raton, Fla. with particular reference to Chapter 2 entitled “Synthesis of The Imidazolinone Herbicides”, pages 8-14 and the references cited therein. The following patent literature references also illustrate the methods that may be used to convert the pyridine diacids, esters and salts to the imidazolinone final products:

U.S. Pat. Nos. 5,371,229; 5,250,694; 5,276,157; 5,110,930; 5,122,608; 5,206,368; 4,925,944; 4,921,961; 4,959,476; 5,103,009; 4,816,588; 4,757,146; 4,798,619; 4,766,218; 5,001,254; 5,021,078; 4,723,011; 4,709,036; 4,658,030; 4,608,079; 4,719,303; 4,562,257; 4,518,780; 4,474,962; 4,623,726; 4,750,978; 4,638,068; 4,439,607; 4,459,408; 4,459,409; 4,460,776; 4,125,727 and 4,758,667, and EP-A 0 041 623.

According to preferred embodiments of the invention conversion of compound (I) to a herbicidal imidazolinone (III) is carried out in analogy to the methods described in EP-A 0 041 623, U.S. Pat. No. 4,518,780 or EP-A 0 144 595.

According to these embodiments compound (I) is first converted to the respective anhydride by known methods, such as reaction with acetic anhydride.

In one embodiment compound (III) is prepared by

-   (i) preparation of a compound (I), where Y is OH, as outlined above; -   (ii-1) conversion of compound (I) to the anhydride (VI),

-   (ii-2) reacting anhydride (VI) with an 2-aminoalkane carboxamide of     formula (VII),

H₂N—CR⁴R⁵—CONH₂  (VII),

-   -   where R⁴ and R⁵ are as in formula (III),     -   to yield amide (VIII),

-   -   where the symbols are as in formula (III),         and

-   (ii-3) condensation of amide (VIII) to yield the herbicidal     imidazolinone (III).

Steps (ii-2) and (ii-3) may be carried out as a one-pot reaction.

In one embodiment step (ii-2) is carried out in analogy to the procedure disclosed in example 10 of EP-A 0 322 616. Compound (I), a substituted 2-aminoalkane carboxamide (VI) and a tertiary amine, preferably triethylamine are reacted in a polar aprotic solvent, such as acetonitrile, to yield an ammonium salt (VIII), which can be acidified to an acid (VIII).

Alternative procedures are disclosed in U.S. Pat. No. 4,518,780 and EP-A 0 144 595. In the latter document the addition of a nitrogen base selected from pyridine, the picolines, quinoline and lutidine is disclosed to improve the regioselectivity of the reaction, i.e. to increase the amount of 2-addition product.

In one embodiment of step (ii-3) amido compound (VIII), preferably in the form of an ammonium salt (R⁶ is HNR₃), is reacted with an alkali metal methoxide, preferably NaOCH₃ in methanol in analogy to example 11 of EP 0 322 616. The resulting suspension is held at reflux until complete conversion. After cooling the mixture is acidified to obtain compound (III) either as the ammonium salt (acidification to a pH of about 4) or the free acid (acidification to pH ≦2).

In a further preferred embodiment, the reaction mixture from step (ii-2) is reacted with methanol (generally 2 to 100 equivalents based on (VIII)) in the presence of an aqueous base (generally 3 to 100 equivalents based on (VIII)), the base being preferably selected from MOH and MOCH₃, where M is an alkali metal, preferably Na or K, particularly Na.

The reaction is carried out at a temperature in the range of from 20 to 120° C., preferably 40 to 90° C. The reaction can be carried out at atmospheric pressure or at elevated pressure, preferably the pressure forming at the desired reaction temperature. The reaction time is generally from 1 to 8 h, preferably from 1 to 5 h.

Isolation of product (III) can be achieved by standard methods. In a preferred embodiment water is added and organic solvents are distilled off. The residue can be taken up in water and acidified, whereupon compound (III) precipitates. After filtration the crude product can be further purified, e.g. by stirring with water or recrystallization.

In a further embodiment compound (III) is prepared by

-   (i) preparation of a compound (I), where Y is OH, as outlined above; -   (ii-1) conversion of compound (I) to the anhydride (VI),

-   (ii-2) reacting anhydride (VI) with aminocarbonitrile (IX),

H₂N—CR⁴R⁵—CN  (IX)

-   -   where R⁴ and R⁵ are as in formula (III),     -   to obtain amidonitrile compound (X),

-   -   where R⁴, R⁵ and R⁶ are as in formula (III),

-   (ii-3) hydrolysis of the nitrile group in compound (X) to yield     amide (VIII),

where the symbols have the same meaning as in formula (III) and

-   (ii-4) condensing amide (VIII) to yield the herbicidal imidazolinone     (III).

Preparation of the anhydride (Vi) can be carried out as described above.

Aminocarbonitriles (IX), which are employed in step (ii-2), are commercially available or can be prepared by methods known in the art. Generally 0.8 to 1.2 equivalents aminonitrile (IX) per equivalent of compound (VI) are used, preferably 0.95 to 1.1.

The reaction is carried out in a solvent, which is preferably selected from aromatic hydrocarbons, preferably toluene, mesitylenes, chlorinated aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene, chlorinated hydrocarbons, such as 1.2-dichloroethane, dichloromethane, acetic acid, and mixtures thereof.

If acetic acid is not used as the main solvent, addition of 0.5 to 4 equivalents, preferably 1 to 3 equivalents (based on compound (I)), is advantageous. Further advantageous additives that improve the selectivity of the ring-opening reaction (2 versus 3 position) are listed in EP-A 0 144 555, and comprise pyridine, 4-picoline, 2-picoline and quinoline.

The reaction is generally carried out at a temperature range of from about 40 to about 120° C., preferably of from about 60 to about 100° C. The reaction time is generally from about 1 to about 3 h.

In a preferred embodiment anhydride (VI) is dissolved in the solvent and brought to the reaction temperature, and aminonitrile (IX) is gradually added. After completion of the reaction and cooling, nitrile compound (X) can be isolated by standard methods.

In a preferred embodiment, however, compound (X) is not isolated but the reaction mixture is directly used in the following hydrolyzation step of the nitrile (step iv-3)

In a typical procedure a slight excess (e.g. 1.1 to 1.5 equivalents based on (X)) of a strong mineral acid, preferably sulfuric acid (preferably in a concentration of 30 to 98%) and water (e.g. 2 to 10 equivalents) are added at a temperature which is generally in the range of about 30 to 120° C., preferably 50 to 90° C. The mixture is further stirred until complete conversion. The reaction time is generally from 1 to 8 h, preferably 1 to 5 h.

Workup and isolation can be achieved by standard methods, such as an aqueous solution (e.g. as its ammonium salt). In a preferred embodiment the reaction mixture is directly used in the following condensation step (ii-4).

In an alternative embodiment hydrolysis of the nitrile group is effected by reaction with aqueous NaOH/H₂O₂ as disclosed, e.g. in EP-A 0 144 595 and U.S. Pat. No. 4,518,780.

Condensation of amido compound (VIII) to the herbicidal imidazolinone may be carried out as described above.

All of the above processes are particularly preferred for the preparation of the compound of formula (III) where Z and Z¹ are H, R⁶ is H, R⁴ is CH₃ and R₅ is CH(CH₃)₂, i.e. imazamox.

The invention is illustrated by the following examples without limiting it thereby.

EXAMPLES Comparative Example 1 Preparation of 5-(methoxymethyl)-2,3-pyridinedicarboxylic acid (According to ex. 3 of EP-A 0 548 532)

A mixture of 25% sodium methoxide in methanol (270 g, 1.25 mol) and [(5,6-dicarboxy-3-pyridyl)-methyl]trimethylammonium bromide, dimethyl ester (Ia) (347 g, 1.00 mol) in methanol (650 ml) is heated at reflux for 1 hour under nitrogen. Water (1 l) and sodium hydroxide (80.0 g, 2.0 mol) are added and the reaction mixture is distilled until the pot is 100-105° C. The reaction mixture is cooled to room temperature, treated with sulfuric acid to adjust the pH to a value from 1.5 to 2 and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to obtain the title product as a white solid (mp 161-162° C.) which is greater than 99% pure by HPLC analysis.

No water is present in the first step of the reaction (methoxylation of the 5-methyl group), which requires a laborious drying or solid isolation process for the starting material. Thus the process is less suitable for industrial application.

Comparative Example 2 Preparation of disodium 5-(methoxymethyl)pyridine-2,3-dicarboxylate from disodium[5,6-(dicarboxylate-3-pyridyl)methyl]trimethylammonium bromide (According to ex. 3 of EP-A 0 747 360)

A mixture of disodium[(5,6-dicarboxylate-3-pyridyl)methyl]trimethylammonium bromide (5.0 g, 13.8 mmol) and a 25% wt/wt solution of sodium methoxide in methanol (4.46 g, 20.7 mmol of NaOCH₃) in 75 g of methanol is heated at 120° C. for 21 hours in a pressure reactor. The reaction is cooled to room temperature, treated with water and concentrated to a final weight of 55.03 g. A 5.0 g sample is assayed by LC analysis (30% CH₃CN, 0.77 M H₃PO₄). The remainder of the reaction solution is evaporated to dryness to give a solid residue, identified by NMR analysis.

In spite of the higher temperature the reaction time is considerably longer than in the inventive process.

Example 1 Preparation of 5-(methoxymethyl)-2,3-pyridinedicarboxylic acid

Bromide (IIa), (0.41 mol) containing about 40% by weight of water, is taken up in methanol. Aqueous NaOH is added over 30 min. at 35° C., and the mixture is stirred for an additional 15 min. NaOCH₃ in methanol is added over 20 min at 45° C.

The reaction mixture is moved to a Parr pressure reactor and heated to the reaction temperature (80 to 100° C.). At about 60° C. the reactor is closed, whereupon pressure builds up reaching about 40 to 45 Psi at the reaction temperature. No external pressure is applied.

After 6 to 8 h, the mixture is cooled and work up is conducted according to known procedures.

E.g. the reaction mixture is cooled to room temperature, treated with sulfuric acid to adjust the pH to a value from 1.5 to 2 and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to obtain the title product as a white solid (mp 161 to 162° C.) which is greater than 99% pure by HPLC analysis.

In a similar fashion examples 2 to 17 shown in Table 1 were carried out.

TABLE 1 % H₂0 after molar molar weight temperature pressure addition of ratio ratio ratio reaction- conversion ex. [° C.] [bar] NaOH NaOMe NaOH MeOH time [h] [%] 2 100 2.76-3.45 48 3 0 3 8.75 99.6 3 100 2.76-3.45 42 5 0 3 8 98.4 4 100 2.76-3.45 61 5 0 3 8 95.2 5 90 1.38-2.07 48 5 0 5 8 91.9 6 80 1.03-1.38 48 5 0 3 8 81.8 7 100 2.76-3.45 55 2 3 5 8 87.5 8 100 2.76-3.45 56 1 4 5 8 92.4 9 100 2.76-3.45 43 1.5 4 5 8 99.7 10  100 2.76-3.45 43 2 4 5 8 100 11  100 2.76-3.45 51 1.5 3 5 8 100 12* 100 2.76-3.45 50 2 2.5 5 8 99.5 13* 100 2.76-3.45 51 1.5 1 6 8 80.0 14  100 2.76-3.45 42 1.5 3 3 5.5 85.0 15  100 2.76-3.45 40 1.5 3 3 6.75 94.0 16  100 2.76-3.45 40 1.5 3 3 8 99.8 17  100 2.76-3.45 37 1.5 3 2 8 99.9 *NaOH added to (II) before H₂O removal under vacuum. MeOH added, then stripped (II), split in 2. NaOMe added just before Parr high temp/press run.

It can be seen that higher temperatures and longer reaction times improve the conversion rate. In addition, conversion is enhanced by a higher amount of base. The process of the invention can be carried out in the presence of large amounts of water as compared to the Comparative Examples.

Example 18 Synthesis of [(5,6-dicarboxy-3-pyridyl)methyl]trimethylammonium bromide, dimethylether (IIa) a) Synthesis of dimethyl 5-(bromomethyl)-2,3-pyridinedicarboxylate (Va) (50% Conversion)

-   -   218.4 g (1.0 mol) compound (Va) were dissolved in 1139.0 g         1,2-dichloroethane (EDC) and 160.0 g water were charged and         heated to 72° C. (about 1-2° C. below reflux). 14.4 g (0.075         mol) 2,2′-azobis(2-methylbutyronitrile) (Vazo 67) in 160.0 g EDC         were added over 2 h at 72° C. After 30 minutes 143.8 g (0.9 mol)         bromine were added over 2 h, under pH control (pH 5-7) by dosage         of about 375.0 g aqueous NaOH (15%). The mixture was stirred         over 1 h for reaction completion (HPLC assay). After cooling to         40° C. the phases were separated.

b) Synthesis of Compound (IIa)

-   -   288.1 g (1.0 mol) compound (IIIa) in mixture with di- and         tribromination byproducts in 3359.0 g EDC (organic phase from         step a, including unreacted compound (IIa) and higher brominated         byproducts) were charged. The mixture was heated to 30° C. and         the vessel evacuated to 200 mbar.     -   70.9 g (1.2 mol) trimethylamine (TMA) was added to the gas phase         during 2 h at 40° C. (closed system). The mixture was stirred         one additional hour (HPLC conversion check: compound (IIIa) in         solution <0.1%).     -   Excess TMA was distilled off together with EDC (mass: 40% of the         EDC mass) transferred to step 2 (1344 g) at 50-55° C. (370-250         mbar). The pH of the distillate was <9. 630.0 g water was         sprayed to the wall so that the solid is dissolved and the         mixture was transferred to the next vessel. The mixture was then         stirred 0.25 h, and the lower organic phase was separated at         40° C. 320.4 g EDC were added. The mixture was stirred and the         lower organic phase was separated at 40° C. The back extraction         was repeated (40° C.) with 320.4 g EDC. The two organic back         extraction phases were combined with the first organic phase and         recycled to the next bromination batch (after addition of 50%         fresh compound (IIa) for a further cycle.

Steps a) and b) were repeated six times. In the last cycle no compound (IVa) was added in step a) and 0.8 mol TMA were added in step b).

The overall conversion rate of compound (IIa) is 96.6%. The yield of compound (IIa) (over 7 cycles) is 77.4% at a purity of >95% (as determined by HPLC). 

1-17. (canceled)
 18. A process for manufacturing a compound of formula (I),

wherein Z is H or halogen; Z¹ is H, halogen, CN or NO₂; Y is OM, and M is an alkali metal or an alkaline earth metal, comprising reacting a compound of formula (II)

wherein Q is a tertiary aliphatic or cyclic, saturated, partially unsaturated or aromatic amine; Z is H or halogen; Z¹ is H, halogen, CN or NO₂; Y¹ and Y² are each independently OR¹, NR¹R², or when taken together Y¹Y² is —O—, —S— or —NR³—; R¹ and R² are each independently H, C₁-C₄ alkyl optionally substituted with C₁-C₄ alkoxy, or phenyl optionally substituted with one to three C₁-C₄ alkyl groups, C₁-C₄ alkoxy groups, or halogen atoms; R³ is H or C₁-C₄ alkyl, in a methanol/H₂O mixture, comprising at least 20% by weight H₂O, based on the sum of water and the compound of formula (II), with a base comprising MOCH₃ and/or MOH, where M is alkali metal or alkaline earth metal, under pressure in a closed vessel at a temperature of from 75 to 110° C.
 19. The process of claim 18, further comprising: (i-1) reacting a compound of formula (IV),

with bromine in the presence of a radical initiator in a solvent mixture comprising an aqueous phase and an organic phase, wherein the organic phase comprises a solvent selected from the group consisting of 1,2-dichloroethane, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene and tetrachloromethane, and where the pH-value of the aqueous phase is from 3 to <8, to obtain a compound of formula (V),

and (i-2) reacting the compound of formula (V) with a tertiary amine Q in a solvent at a temperature range of 0 to 100° C. to the compound of formula (II), and (i-3) reacting the compound of formula (II) in a methanol/H₂O mixture, with a base comprising MOCH₃ and MOH, where M is alkali metal, under pressure in a closed vessel at a temperature of from 75 to 110° C.
 20. The process of claim 18, wherein the compound of formula (II) is the compound (IIa)


21. The process of claim 18, wherein the ratio of methanol to compound of formula (II) is in the range of from 0.5-25:1.
 22. The process of claim 18, wherein the base is a mixture of MeOM and MOH.
 23. The process of claim 18, wherein the base is MeOM.
 24. The process of claim 22, wherein the molar ratio of MeOM to compound of formula (II) is in the range of from 1-10:1.
 25. The process of claim 23, wherein the molar ratio of MeOM to compound of formula (II) is in the range of from 1-10:1.
 26. The process of claim 18, wherein the base is MOH.
 27. The process of claim 22, wherein the molar ratio of MOH to compound of formula (II) is in the range of from 0.5-10:1.
 28. The process of claim 26, wherein the molar ratio of MOH to compound of formula (II) is in the range of from 0.5-10:1.
 29. The process of claim 18, wherein the molar ratio of total amount of base added to the compound of formula (II) is 3-7:1.
 30. The process of claim 18, wherein the reaction temperature is in the range of from about 75 to 110° C.
 31. The process of claim 18, which is carried out at a pressure of 1.01 to 5.00 bar.
 32. A process for preparing a compound of formula (III),

wherein Z is H or halogen; Z¹ is H, halogen, CN or NO₂; R⁴ is C₁-C₄ alkyl; R⁵ is C₁-C₄ alkyl, C₃-C₆ cycloalkyl or R⁴ and R⁵, when taken together with the atom to which they are attached, represent a C₃-C₆ cycloalkyl group optionally substituted with methyl, and R⁶ is hydrogen; a group of the formula —N═C (lower alkyl)₂; C₁-C₁₂ alkyl optionally substituted with one of the following groups: C₁-C₃ alkoxy, halogen, hydroxyl, C₃-C₆-cycloalkyl, benzyloxy, furyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyl, lower alkoxycarbonyl, cyano or tri lower alkylammonium; C₃-C₁₂ alkenyl optionally substituted with one of the following groups: C₁-C₃ alkoxy, phenyl, halogen or lower alkoxycarbonyl or with two C₁-C₃ alkoxy groups or two halogen groups; C₃-C₆ cycloalkyl optionally substituted with one or two C₁-C₃ alkyl groups; or a cation; comprising: (i) preparing the compound of formula (I) according to claim 18; (ii) converting the compound of formula (I) into the compound of formula (III).
 33. The process of claim 32, further comprising: (i) preparating the compound (I), where Y is OH, (ii-1) converting the compound (I) to the compound of formula (VI),

wherein Z is H or halogen; Z¹ is H, halogen, CN or NO₂; (ii-2) reacting the compound of formula (VI) with a compound of formula (VII), H₂N—CR⁴R⁵—CONH₂  (VII), wherein R⁴ is C₁-C₄ alkyl; R⁵ is C₁-C₄ alkyl, C₃-C₆ cycloalkyl or R⁴ and R⁵, when taken together with the atom to which they are attached, represent a C₃-C₆ cycloalkyl group optionally substituted with methyl, to yield a compound of formula (VIII),

and (ii-3) condensing the compound of formula (VIII) to yield the compound of formula (III).
 34. The process of claim 32, further comprising: preparing the compound (I), where Y is OH; (ii-1) converting the compound of formula (I) to the compound of formula (VI),

(ii-2) reacting the compound of formula (VI) with a compound of formula (IX), H₂N—CR⁴R⁵—CN  (IX); to obtain a compound of formula (X),

(ii-3) hydrolyzing the compound of formula (X) to yield a compound of formula (VIII),

and (ii-4) condensing the compound of formula (VIII) to yield the compound of formula (III). 